The overall goal of this project is to understand the functional neuroanatomical bases of nicotine dependence through examination of the neural substrates underlying adaptations to chronic and cute nicotine exposure as well as vulnerability to nicotine dependence. We propose an endophenotypic study of sib-pairs discordant and concordant for smoking phenotypes that represent differing degrees of lifetime tobacco use. Targeted pairs will include: 30 current smoker/ever smokers, 30 former smoker/ever smokers, and 30 ever smoker/ever smoker (ever smoker denotes exposure to cigarettes but no progression to regular smoking). This allows partitioning of genetic/environmental vulnerability (seen in probands and siblings by smoking status of the proband) from chronic nicotine exposure (seen only in probands by smoking status). Assessment will include a repeated measures fMRI protocol with and without nicotine challenge to permit examination of brain function according to acute nicotine exposure as well as genetic/environmental vulnerability and chronic nicotine exposure. We will assess differences in regional brain tMRI brain oxygen level dependent (BOLD) signal activation in response to four tasks including two cognitive challenges tapping behavioral inhibition (stop signal task) and verbal working memory (2-Back task), a cue-provocation paradigm, designed to elicit a state of craving, and an emotion processing task. Specific regions of interest (ROI) include: the amygdala, nucleus accumbens, caudate nucleus, and specific areas of the prefrontal cortex. We expect: 1) Brain response to smoking and emotional cues will be greater during nicotine abstinence compared to nicotine intake, particularly among current smokers. 2) Activation of ROIs will increase and behavioral performance will improve following nicotine intake regardless of smoking history. 3)Current smokers will exhibit significant decrements in performance and reductions in activation of ROIs during nicotine abstinence. 4) Sibs of current smokers will exhibit worse attentional processing and less behavioral inhibition in during nicotine abstinence and greater cue-elicited craving and activation of ROls than sibs of former and ever smokers. We expect no relative activation in response to smoking cues in ever smoker sib pairs. Results should lead to the development of a comprehensive model of the functional neuroanatomic basis of nicotine dependence, from processes maintaining the nicotine dependence cycle to those mediating vulnerability to nicotine dependence.